Obstructive sleep apnea (OSA) is a breathing disorder that affects at least 4% of the adult population. Beside daytime sleepiness, OSA has been implicated in the pathogenesis of cardiovascular diseases, including systemic and pulmonary hypertension, coronary artery disease, congestive heart failure, stroke, cardiac arrhythmias, and sudden cardiac death. The mechanisms by which OSA affects the cardiovascular system may result from excursions in intrathoracic pressure, increased sympathetic activation, and subsequent intermittent hypoxia (IH). IH induces endothelial dysfunction via oxidative stress by increased generation of reactive oxygen species (ROS), inflammation, and impairment of the activity of endothelial nitric oxide synthase (eNOS), an enzyme responsible for generation of nitric oxide, whose bioavailability is key for proper function of the endothelium. Even though OSA is a fairly well investigated disease, the mechanistic insights into OSA effects on the vasculature remain to be elucidated. We have recent evidence that extracellular nucleotides, such as ATP, ADP and UTP, acting via specific P2 purinergic receptors, decrease high glucose- induced ROS formation, attenuate inflammatory effects of tumor necrosis factor alpha, and rescue eNOS activity in human endothelial cells cultured in high glucose concentrations. Our new in vivo data indicate that ATP administration decreases the expression of oxidative stress-related and proinflammatory proteins in aortic arches of diabetic, atherosclerosis-prone ApoE-deficient mice. Given the similarity in molecular targets of high glucose and IH in the vasculature, we hypothesize that the protective effects of purinergic signaling observed in endothelial cells exposed to high glucose could also be pertinent to patients with OSA. This grant proposal is aimed at elucidating the molecular basis of the beneficial effects of P2 receptor signaling, and providing an in vivo proof of principle for extracellular nucleotide effectiveness in preventing vasculopathy associated with intermittent hypoxia, as a model of sleep apnea. We propose that extracellular nucleotides protect the endothelium from the damaging effects of IH by maintaining adequate eNOS function, decreasing ROS generation, and by attenuating proinflammatory signaling. Finding of new therapeutic targets for OSA-related complications are urgently required. We suggest that P2 receptors are a promising target for the protection of vasculature from oxidative stress and inflammation, such as those observed in OSA. PUBLIC HEALTH RELEVANCE: Obstructive sleep apnea is a breathing disorder that affects at least 4% of the adult population. Numerous data point to the association of sleep apnea and cardiovascular morbidity and mortality, and in addition link sleep apnea with obesity and with markers of the metabolic syndrome. We propose a novel approach to protect vasculature from deleterious effects of obstructive sleep apnea.